Comparison of the cardiac effects of the antimalarials co-artemether and halofantrine in healthy participants.

Abstract

Abstract. Co-artemether (Coartem, Riamet) is a tablet containing 20 mg artemether and 120 mg lumefantrine for treatment of falciparum malaria. Lumefantrine has some chemical similarities to halofantrine (Halfan), an antimalarial known for QTc prolongation. Effects on the QTc interval of fed single oral doses of 500 mg halofantrine and 80/480 mg co-artemether were compared in 13 healthy males in a randomized double-blind crossover study. Electrocardiograms (ECGs) were recorded from 48 hours before dosing until 48 hours thereafter. The maximum QTc interval (QTc ‫ס‬ QT/√RR) was compared before and after treatment and between treatments, fitting a general linear model. Drug plasma concentrations were determined concomitantly. After halofantrine, all participants showed an increase in the QTc interval; the mean maximum increase was 28 ms. The length of the QTc interval was positively correlated to halofantrine exposure. The QTc interval remained unchanged after co-artemether. The difference between treatments was statistically significant. In conclusion, halofantrine caused a significant, exposure-dependent increase in the QTc interval. No such effect was seen with co-artemether.Malaria is the cause of considerable morbidity and mortality in the developing world, and there is a clear need for new treatments, particularly as resistance to available drugs is increasing. 1,2Co-artemether (Coartem, Riamet), which was developed in China for the treatment of falciparum malaria, is an oral preparation containing 20 mg artemether and 120 mg lumefantrine (previously known as benflumetol) per tablet. Artemether, an artemisinin derivative, is characterized by a rapid onset of schizontocidal action resulting in fast relief from fever and fast parasite clearance. However, recrudescence is frequent when provided as a single agent, unless given for at least 5-7 days.3-6 By contrast, lumefantrine has a high cure rate when administered as a short treatment course of 2-3 days duration, but parasite and fever clearance is much slower than with artemether. Co-artemether combines the treatment advantages of both drugs, providing a short and simple antimalarial treatment likely to improve compliance. In areas of multidrug resistance and in nonimmune patients, the recommended dose regimen is 6 doses of 4 tablets each (80 mg artemether and 480 mg lumefantrine per dose) given over 60 hours. Otherwise, the recommended dose regimen is 4 doses of 4 tablets over 2 days.Halofantrine (Halfan) is one of the antimalarial compounds causing QTc prolongation at standard therapeutic doses (3 doses of 500 mg given at 6-hour intervals). Because lumefantrine has some chemical similarities to halofantrine, and QTc prolongation was reported after high-dose intramuscular treatment with artemether in animal experiments 7 and in a clinical study in patients with severe malaria, 8 a careful evaluation of co-artemether with regard to cardiac effects, particularly on the QTc interval, was warranted.In the current study, the potential cardiac effects of coartemethe...

Optimizing the programmatic deployment of the anti-malarials artemether-lumefantrine and dihydroartemisinin-piperaquine using pharmacological modelling

“…Some AEs are dose-independent and would occur at a constant rate irrespective of the used dosing regimen, e g, in a pooled analysis of individual patient data vomiting or diarrhoea were not correlated with the mg/kg dose of PPQ [39]. Others are dose-dependent and correlated with PK factors, such as the total AUC and the maximum concentration reached (c max ), e g, the length of the corrected interval between the Q and T wave in the heart’s electrical cycle is positively correlated with halofantrine exposure [55], glucose-6-phosphate dehydrogenase (G6PD) deficiency mediates dose-related toxicity in primaquine [56] and pruritus in sensitive individuals is linked to chloroquine levels [57]. It is of note that the between-subject variability in human PK parameters is typically 30–50% [58].…”

Proarrhythmic Potential of Antimicrobial Agents

“…Artemether-lumefantrine did not alter the QT c interval in a study of 13 healthy subjects [83]. Coartemether may be used following failure of antimalarial prophylaxis or treatment with mefloquine.…”

In Vitro Cardiovascular Effects of Dihydroartemisin-Piperaquine Combination Compared with Other Antimalarials

“…The combination of DHA at two concentrations (2.4 and 7.2 M) in the presence of PQP was also evaluated, and hERG blockade by DHA-PQP was less than that by PQP alone. However, retrospective analysis of the risk of TdP and the ability of a drug to inhibit this channel demonstrates that some compounds already on the market can block this channel without inducing TdP (6,41). It is generally accepted that hERG blockade can predict clinical QT prolongation in many cases but not TdP (19,34,40).…”